title: Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer.
abstract: OBJECTIVE
  Lapatinib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR/ErbB1) and human epidermal growth factor receptor 2 (HER-2/ErbB2), is effective against HER-2-positive locally advanced or metastatic breast cancer (MBC). This phase III trial evaluated the efficacy of lapatinib in HER-2-negative and HER-2-uncharacterized MBC.
  
  
  METHODS
  Women with MBC were randomly assigned to first-line therapy with paclitaxel 175 mg/m(2) every 3 weeks plus lapatinib 1,500 mg/d or placebo. A preplanned retrospective evaluation of HER-2 status was performed using fluorescence in situ hybridization and immunohistochemistry. The primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), clinical benefit rate (CBR), event-free survival (EFS), and overall survival (OS).
  
  
  RESULTS
  In the intent-to-treat population (n = 579), there were no significant differences in TTP, EFS, or OS between treatment arms, although differences in ORR and CBR were noted. In 86 HER-2-positive patients (15%), treatment with paclitaxel-lapatinib resulted in statistically significant improvements in TTP, EFS, ORR, and CBR compared with paclitaxel-placebo. No differences between treatment groups were observed for any end point in HER-2-negative patients. The most common adverse events were alopecia, rash, and diarrhea. The incidence of diarrhea and rash was significantly higher in the paclitaxel-lapatinib arm. The rate of cardiac events was low, and no difference was observed between treatment arms.
  
  
  CONCLUSIONS
  Patients with HER-2-negative or HER-2-untested MBC did not benefit from the addition of lapatinib to paclitaxel. However, first-line therapy with paclitaxel-lapatinib significantly improved clinical outcomes in HER-2-positive patients. Prospective evaluation of the efficacy and safety of this combination is ongoing in early and metastatic HER-2-positive breast cancer patients.
authors.affiliation: Sandro Pitigliani Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy 59100. adileo@usl4.toscana.it
authors.forename: Angelo
authors.initials: A
authors.lastname: Di Leo
authors.forename: Henry L
authors.initials: HL
authors.lastname: Gomez
authors.forename: Zeba
authors.initials: Z
authors.lastname: Aziz
authors.forename: Zanete
authors.initials: Z
authors.lastname: Zvirbule
authors.forename: Jose
authors.initials: J
authors.lastname: Bines
authors.forename: Michael C
authors.initials: MC
authors.lastname: Arbushites
authors.forename: Stephanie F
authors.initials: SF
authors.lastname: Guerrera
authors.forename: Maria
authors.initials: M
authors.lastname: Koehler
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliva
authors.forename: Steven H
authors.initials: SH
authors.lastname: Stein
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Williams
authors.forename: Judy
authors.initials: J
authors.lastname: Dering
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.forename: Michael F
authors.initials: MF
authors.lastname: Press
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage*; D010919:Placebos; D011799:Quinazolines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D012189:Retrospective Studies
chemical_list: D000077341:Lapatinib; D017239:Paclitaxel; D010919:Placebos; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases